European Published Patent Application 0399556, which is herein incorporated by reference, discloses a novel series of amino-substituted heterocycles.
The compounds disclosed in European Published Patent Application 0399556 are useful for treating renin-associated hypertension, congestive heart failure, glaucoma, hyperaldosteronism, diseases caused by retroviruses including HTLV I, II, and III, as well as the use of the compounds as diagnostic tools for determining the presence of renin-associated hypertension or hyperaldosteronism. Particularly valuable in the aforementioned therapeutic categories and in particular in the treatment of renin-associated hypertension is [1S -(1R*,2S*,3R*)]-N-(4-morpholinylsulfonyl)-L-phenylalanyl-3-(2-amino-4-thia zolyl) -N-[1-(cyclohexymethyl)-2,3-dihydroxy-5-methylhexyl]-L-alaninamide. The aforementioned compound has been prepared by a procedure utilizing 3-(2-amino-4-thiazolyl)-L-alanine as a key intermediate. The amino group on the thiazole ring of this intermediate was protected to prevent by-products resulting from coupling through the aminothiazole group. Additionally, the process requires an expensive starting material, uses potentially hazardous reagents and intermediates, and finally involves the use of chromatography for purification of intermediates and final product.
The object of the present invention is an improved process for preparing the compound described above by using a novel synthesis.
Further, we have unexpectedly found that the key intermediate, 3-(2-amino-4-thiazolyl)-L-alanine can be used in the present procedure without protecting the aminothiazole group. Thus, the present method eliminates two steps required for protection and removal of the blocking group on the aminothiazole group. Moreover, the present method proceeds from an inexpensive starting material, uses nonhazardous reagents and finally does not require chromatography to purify intermediates and final product. Therefore, the present process is amenable to large-scale synthesis.